Immune therapy involves the exposure of components of the immune system to various elements (cytokines, disease associated antigens and natural metabolites) to combat disease processes in which a non-regulated immune response is thought to play a role. Immune dysregulation is thought to play a major part in the pathogenesis or disease course of a great number of disease processes, including various neoplastic, inflammatory, infectious and genetic entities.
The Role of Fungi in the Modulation of the Immune System.
Lentinula, Pleurotus, Auricularia, Flammulina, Tremella, Hericium, and Grifola fungi have various degrees of immunomodulatory, lipid-lowering, antitumor beneficial or therapeutic effects without any significant toxicity.
Fungi have been valued by humans as an edible and medical resource. Fungi have long been known for their nutritious benefits. They are an excellent source of selenium, riboflavin, pantothenic acid copper, niacin, potassium and phosphorous. In particular selenium is needed for proper function of important antioxidants which work to reduce the levels of damaging free radicals in the body. Fractions from medical fungi were used as medicine in the Far East. Extracts and isolated metabolites from fungi can modulate immune responses [Lull, C. et al., Mediators Inflamm. 2005:63-80 (2005)]. This can result in an enhanced innate and acquired disease resistance. The major immunomodulating effects of these active substances derived from fungi include mitogenicity and activation of immune effector cells, such as lymphocytes, macrophages, and natural killer cells, resulting in the production of cytokines, including interleukins (ILs), tumor necrosis factor alpha (TNF-α, and interferon gamma (IFN-γ) [Lull et al. (2005), Ibid.]. The ability of selective fungal extracts to modulate the differentiation capacity of CD4(+) T cells to mature into Th1 and/or Th2 subsets has been shown recently.
Previous data suggested that these extracts may have profound effects in Th1 or Th2 immune-mediated disorders [Inoue, A. et al., Biol. Pharm. Bull. 25:536-540 (2002)]. A number of bioactive molecules, most of them polysaccharides, with antitumoral properties indicating induction of a Th1 response, have been identified in many mushroom-derived formulations [Moradali, M. F. et al., Int. Immunopharmacol. 7:701-724 (2007)].
The major immune modulating effects of these active substances include mitogenicity and activation of immune effector cells, such as lymphocytes, macrophages and Natural Killer T (NKT) cells.
Fungal derivates can affect different parts of the immune system, including macrophage activation by induction of TNF-α, IL-6 and IL-1, dendritic cell activation and various effects on T cells [Moradali et al. (2007), Ibid.]. Lentinula edodes was described as T-cell oriented adjuvant, skewing the Th1/Th2 balance to Th1 by distinctive induction of IL-12 from activated macrophages [Wasser S. P., Appl. Microbiol. Biotechnol. 60:258-274 (2002)].
The Role of Shiitake in Immuno-Modulation.
Lentinan, a (1-3)-beta glucan from Lentinula edodes, is licensed as an immunostimulatory drug [Kupfahl, C. et al., Int. Immunopharmacol. 6:686-696 (2006)]. Pre-treatment of mice with lentinan resulted in increased concentrations of TNF-α, IL-12 and IFN-γ and also an increased number of Listeria monocytogenes specific CD8 T cells in the spleen. The bacterial burden in spleen and liver of mice was significantly reduced during primary and secondary Listeria infection after lentinan pre-treatment of mice. Lentinula edodes (Shiitake) and its active component, the polysaccharide lentinan were found effective against various tumors. The mechanism of its action is not understood. Several studies showed its efficacy in various gastrointestinal tumors, gynecologic tumors, as well as leukemia and lymphoma. In most of these studies Shiitake augments the effect of other drugs.
It was suggested that mushrooms do not attack cancer cells directly, but produce their anti-tumor effects by activating different immune responses in the host [Yvin, J. C., Int. Immunopharmacol, 4:721-730 (2004)]. Shiitake was also shown to be a hepatoprotective and anti-fibrotic agent. In dimethylnitrosamine-induced hepatitis, Shiitake decreased the blood levels of aminotransferases by inhibiting the over accumulation of collagen fibrils and suppressed the over expression of genes for alpha-smooth muscle actin and heat-shock protein 47 [Akamatsu, S. et al., Biol. Pharm. Bull. 27:1957-1960 (2004)]. Shiitake also inhibited the morphologic change and proliferation of isolated rat hepatic stellate cells (HSCs), which play a central role in liver fibrosis, in a dose-dependent manner and without cytotoxicity [Akamatsu et al. (2004), Ibid.]. Interestingly the hepatoprotective effects of Shiitake were also observed after oral administration [Watanabe, A. et al., Biol. Pharm. Bull. 29:1651-1654 (2006)]. In a D-galactosamine (GalN)-induced liver injury model in rats oral administration of Shiitake caused less leakage of aminotransferases and improves the degree of histological injury [Watanabe et al. (2006), Ibid.]. As a result, several studies were conducted, in order to characterize the specific active component, and its immune modulating effect however, this effect was never tested in immune mediated disorders [Vetvicka, V. et al., Biomed. Pharmacother. 2008 June; 62(5) 283-8].
WO 2006/007848 showed that polypeptides and polysaccharides produced by the fungus and secreted to the extracellular environment of the liquid growth medium exhibit an immune modulatory effect towards a pro-inflammatory response which may be beneficial in the treatment of immune compromised patients.
The Role of the Liver in Immune System Processes.
The role of liver in the pathogenesis of different immune mediated disorders is well known. The liver contains a mixture of lymphocytes consisting of both conventional T and B cells, and a distinct population of resident liver lymphocytes. Furthermore the liver is a specific site for trapping and destruction of activated T cells. The exact role of the liver in immune cell trapping and destruction is not fully understood, one theory suggests that cells that are already starting apoptosis process are sequestrated in the liver. The second theory suggest that the liver has an active role in the immune process by destructing activated T cells due to a local tolerance mechanism that causes clonal deletion.
Vitamin D is a Known Immune Modulator.
Beyond its critical function in calcium homeostasis, vitamin D has recently been found to play an important role, in the modulation of the immune/inflammation system, via regulating the production of inflammatory cytokines and inhibiting the proliferation of proinflammatory cells, both of which are crucial for the pathogenesis of inflammatory diseases. Several studies have associated lower vitamin D status with increased risk and unfavorable outcome of acute infections. Vitamin D supplementation bolsters clinical responses to acute infection. Moreover, chronic inflammatory diseases, such as atherosclerosis-related cardiovascular disease, asthma, inflammatory bowel disease, chronic kidney disease, nonalcoholic fatty liver disease, and others, tend to have lower vitamin D status, which may play a pleiotropic role, in the pathogenesis of the diseases.
Vitamin D is associated with enhancement of anti-inflammatory IL-10 secretion by CD4+ Treg cells in Steroid-resistant Asthma patients (Xystrakis et. al., Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J. Clin. Invest. (2006) 116:146-155); Suppression of pro-inflammatory IL-2, TNF-α, and IFN-γ secretion by Th1 cells (Smyk et. al., Vitamin D in autoimmune liver disease. Clin Res Hepatol Gastroenterol (2013) 37(5):535-545); Induction of immune tolerance by promotion of tolerogenic dendritic cell function (Agmon-Levin et. al. Vitamin D in Systemic and Organ-Specific Autoimmune Diseases. Clinic Rev Allerg Immunol (2013) 45:256-266); Induction of macrophage response to TB infections (Shapora et. al., Mycobacterium Tuberculosis, Autoimmunity, and Vitamin D. Clinic Rev Allerg Immunol (2010) 38:169-177); and decreased proliferation and antibody production by B cells (Chen et. al. Modulatory Effects of 1,25-Dihydroxyvitamin D3 on Human B Cell Differentiation. J Immunol (2007) 179:1634-1647).
Mushrooms have relatively high levels of ergosterol, which, under the action of UV light gets converted to ergocalciferol (known as vitamin D2) [Kalaras et al., J. Agric. Food Chem. 2012. 60: 220-225; DE202010016402; U.S. Pat. No. 8,545,915; US20110091579; CA2759246]. Vitamin D2 is inactive, but on consumption is converted to 25-hydroxycholecalciferol in the liver, then to 1,25-dihydroxycholecalciferol (vitamin D3) by the kidneys.
There remains an unmet need for improved fungi or fungi-derived products that could be used for treatment of immune-related disorders.